Dual effects of radiotherapy on tumor microenvironment and its contribution towards the development of resistance to immunotherapy in gastrointestinal and thoracic cancers

Abstract

Successful clinical methods for tumor elimination include a combination of surgical resection, radiotherapy, and chemotherapy. Radiotherapy is one of the crucial components of the cancer treatment regimens which allow to extend patient life expectancy. Current cutting-edge radiotherapy research is focused on the identification of methods that should increase cancer cell sensitivity to radiation and activate anti-cancer immunity mechanisms. Radiation treatment activates various cells of the tumor microenvironment (TME) and impacts tumor growth, angiogenesis, and anti-cancer immunity. Radiotherapy was shown to regulate signaling and anti-cancer functions of various TME immune and vasculature cell components, including tumor-associated macrophages, dendritic cells, endothelial cells, cancer-associated fibroblasts (CAFs), natural killers, and other T cell subsets. Dual effects of radiation, including metastasis-promoting effects and activation of oxidative stress, have been detected, suggesting that radiotherapy triggers heterogeneous targets. In this review, we critically discuss the activation of TME and angiogenesis during radiotherapy which is used to strengthen the effects of novel immunotherapy. Intracellular, genetic, and epigenetic mechanisms of signaling and clinical manipulations of immune responses and oxidative stress by radiotherapy are accented. Current findings indicate that radiotherapy should be considered as a supporting instrument for immunotherapy to limit the cancer-promoting effects of TME. To increase cancer-free survival rates, it is recommended to combine personalized radiation therapy methods with TME-targeting drugs, including immune checkpoint inhibitors.

Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy

“…As aforementioned above, many exosomes-based mechanisms underlying evasion of immune surveillance confer to resistance to immunotherapy including ICT [ 206 , 230 , 231 ], and CAR-T therapy in cancer as well [ 247 ]. In addition, reshaped TME resulted from conventional treatment such as radiotherapy, as well as ICT has also been increasingly recognized as key player in development of acquired resistance to cancer immunotherapy [ 392 , 393 ], which adding new dimension to the field of even complicated exosome-mediated mechanisms [ 394 ].…”

A new target of radiotherapy combined with immunotherapy: regulatory T cells

“…It can also cause TME hypoxia and induce TGF-β expression on tumour cells to trigger hypoxia-inducible factor 1(HIF-1)/vascular endothelial growth factor (VEGF) pathway to promote tumour angiogenesis ( 13 , 14 ). Radiotherapy can induce cancer-associated fibroblasts (CAFs) to secrete various growth factors, such as transforming growth factor β(TGF-β) and matrix metalloproteinases (MMPs), then further promote tumour growth ( 15 ) ( Figure 1 ).…”